Herlitz's junctional epidermolysis bullosa is linked to mutations in the gene (LAMC2) for the γ2 subunit of nicein/kalinin (LAMININ–5)

Aberdam, Daniel; Mf, Galliano; Vailly, Joëlle; Pulkkinen, Leena; Bonifas, Jeannette M.; Christiano, A. M.; Tryggvason, Karl; Uitto, Jouni; Epstein, Ernst; Jp, Ortonne

doi:10.1038/ng0394-299

Cited by 325 publications

(166 citation statements)

References 25 publications

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“…1,5,6) Mutation or deletion of the LN-5 genes (LAMA3, LAMB3, and LAMC2) is associated with epidermolysis bullosa, a lethal skin blistering disease. [7][8][9] LN-5 strongly promotes adhesion, migration, and scattering of various types of cultured cells compared with other extracellular matrix proteins. 4,10,11) The expression of LN-5 in tumor cells is stimulated by growth factors and a tumor promoter in vitro.…”

Section: Abstract: Laminin-5 -Laminin γ2 Chain -Lung Adenocarcinoma mentioning

confidence: 99%

Sole Expression of Laminin γhain in Invading Tumor Cells and Its Association with Stromal Fibrosis in Lung Adenocarcinomas

Kagesato

Mizushima

Koshikawa

et al. 2001

Japanese Journal of Cancer Research

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Section: Abstract: Laminin-5 -Laminin γ2 Chain -Lung Adenocarcinoma mentioning

confidence: 99%

Sole Expression of Laminin γhain in Invading Tumor Cells and Its Association with Stromal Fibrosis in Lung Adenocarcinomas

Kagesato

Mizushima

Koshikawa

et al. 2001

Japanese Journal of Cancer Research

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“…In epider-*Corresponding author. Fax: (358) (81) 553 1151. molysis bullosajunctionalis, a skin blistering disease, mutations were described in the human gene (LAMC2) for the 7/2 chain [33,34] demonstrating that this hemidesmosomal protein is essential for attachment of epithelial cells. A mutation was recently also described in the gene for the c~2 chain (LAMA2) [35], in dy mice with muscular dystrophy, indicating that this chain is important for differentiation or function of muscle fibers.…”

Section: Introductionmentioning

confidence: 99%

Primary structure and expression of a novel human laminin α4 chain

et al. 1995

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The complete primary structure of a novel human laminin a4 chain was derived from eDNA clones. The translation product contains a 24-residue signal peptide preceding the mature a4 chain of 1792 residues. The domain structure is similar to that of the recently described a3 chain [Ryan, Tizard, Van Devanter and Carter (1994) J. Biol. Chem. 269, 22779-227871. Northern analysis of RNA from human fetal and adult tissues revealed developmental regulation of expression. In adult, strong expression was observed in heart as well as lung, ovary, small and large intestines, placenta and liver, whereas weak or no expression was detected in skeletal muscle, kidney, pancreas, testis, prostate or brain. In contrast, fetal lung and kidney revealed high expression. In situ hybridization analysis of human fetal and newborn tissues showed expression of the laminin in or4 chain in certain mesenchymal cells in tissues such as smooth muscle and dermis.

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“…The crucial importance of the interaction between laminin-5 and its ␣ 6 ␤ 4 receptor in maintaining the integrity of the integument has been unambiguously proven by the generation of ␣ 6 -and ␤ 4 -null mice (10 -12) and by the identification of gene mutations in patients suffering from a devastating blistering disorder of the skin known as junctional epidermolysis bullosa (JEB). In most cases, JEB is due to mutations in LAMA3, LAMB3, and LAMC2 genes (13)(14)(15) and in ITGA6 and ITGB4 genes, which encode ␣ 6 and ␤ 4 integrin subunits, respectively (16,17). Mutations in ITGA6 and ITGB4 are usually associated to pyloric atresia (PA)-JEB (16,17).…”

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Gene Correction of Integrin β4-dependent Pyloric Atresia-Junctional Epidermolysis Bullosa Keratinocytes Establishes a Role for β4 Tyrosines 1422 and 1440 in Hemidesmosome Assembly

Dellambra¹,

Prislei²,

Salvati³

et al. 2001

Journal of Biological Chemistry

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The cytoplasmic domain of ␤ 4 integrin contains two pairs of fibronectin-like repeats separated by a connecting segment. The connecting segment harbors a putative tyrosine activation motif in which tyrosines 1422 and 1440 are phosphorylated in response to ␣ 6 ␤ 4 binding to laminin-5. Primary ␤ 4 -null keratinocytes, obtained from a newborn suffering from lethal junctional epidermolysis bullosa, were stably transduced with retroviruses carrying a full-length ␤ 4 cDNA or a ␤ 4 cDNA with phenylalanine substitutions at Tyr-1422 and Tyr-1440. Hemidesmosome assembly was evaluated on organotypic skin cultures. ␤ 4 -corrected keratinocytes were indistinguishable from normal cells in terms of ␣ 6 ␤ 4 expression, the localization of hemidesmosome components, and hemidesmosome structure and density, suggesting full genetic and functional correction of ␤ 4 -null keratinocytes. In cultures generated from ␤ 4 Y1422F/Y1440Fkeratinocytes, ␤ 4 mutants as well as ␣ 6 integrin, HD1/ plectin, and BP180 were not concentrated at the dermalepidermal junction. Furthermore, the number of hemidesmosomes was strikingly reduced as compared with ␤ 4 -corrected keratinocytes. The rare hemidesmosomes detected in ␤ 4 Y1422F/Y1440F cells were devoid of subbasal dense plates and of inner cytoplasmic plaques with keratin filament insertion. Collectively, our data demonstrate that the ␤ 4 tyrosine activation motif is not required for the localization of ␣ 6 ␤ 4 at the keratinocyte plasma membrane but is essential for optimal assembly of bona fide hemidesmosomes.Human epidermis consists of a stratified squamous epithelium composed of keratinocytes organized in distinct cellular layers. Keratinocytes forming the basal layer firmly adhere to the basement membrane by means of hemidesmosomes (HDs), 1 multiprotein complexes linking the epithelial intermediate filament network to the dermal anchoring fibrils (see Refs. 1 and 2 for review). HDs are formed by the clustering of several cytoplasmic and trans-membrane proteins (2). The cytoplasmic HD plaque components, which include HD1/plectin (3) and the bullous pemphigoid antigen 1 (BP230) (4), act as linkers for elements of the cytoskeleton at the cytoplasmic surface of plasma membrane. The trans-membrane constituents of HDs, which include the ␣ 6 ␤ 4 integrin (5, 6) and the bullous pemphigoid antigen 2 (BP180) (7), serve as cell receptors connecting the cell interior to extracellular matrix proteins.In particular, the ␣ 6 ␤ 4 integrin is a receptor for the basement membrane component laminin-5, a heterotrimeric protein composed of three distinct polypeptides, ␣3, ␤3, and ␥2, which are encoded by three different genes known as LAMA3, LAMB3, and LAMC2, respectively (see Ref. 8 for review). Laminin-5 binds to the basal keratinocyte cell surface through the ␣ 6 ␤ 4 integrin and tightens the dermal-epidermal junction by binding also to the N-terminal NC-1 domain of type VII collagen (9). The crucial importance of the interaction between laminin-5 and its ␣ 6 ␤ 4 receptor in maintaining the integrity of the i...

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Herlitz's junctional epidermolysis bullosa is linked to mutations in the gene (LAMC2) for the γ2 subunit of nicein/kalinin (LAMININ–5)

Cited by 325 publications

References 25 publications

Sole Expression of Laminin γhain in Invading Tumor Cells and Its Association with Stromal Fibrosis in Lung Adenocarcinomas

Sole Expression of Laminin γhain in Invading Tumor Cells and Its Association with Stromal Fibrosis in Lung Adenocarcinomas

Primary structure and expression of a novel human laminin α4 chain

Gene Correction of Integrin β4-dependent Pyloric Atresia-Junctional Epidermolysis Bullosa Keratinocytes Establishes a Role for β4 Tyrosines 1422 and 1440 in Hemidesmosome Assembly

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